CENTRO DE INVESTIGACIONES CARDIOVASCULARES "DR. HORACIO EUGENIO CINGOLANI"
Unidad Ejecutora - UE
congresos y reuniones científicas
CaMKII regulation of Na+/H+ exchanger function
MUNDIÑA - WEILENMANN C
Congreso; XX Congreso Mundial de la International Society for Heart Research; 2010
International Society for Heart Research
The control of intracellular pH (pHi) is a fundamental process required to preserve normal cell function. In cardiac myocytes, acids generated metabolically within the cell are primarily removed by the type 1 isoform of the Na+-H+ exchanger (NHE-1). NHE-1 couples H+ efflux to Na+ influx under the driving force of a Na+ gradient. The regulation of NHE-1 activity involves modification of the intracellular carboxyl-terminal regulatory domain, either by binding to accessory proteins and/or by excitatory and inhibitory phosphorylations. Ca2+/calmodulin-dependent protein kinase II (CaMKII) is one of the kinases proposed to phosphorylate the exchanger. However the impact of CaMKII on NHE-1 activity is still held as a question mark. Using highly specific genetic approaches (adenoviral gene transfer and transgenic mice) to precisely manipulate CaMKII activity, we provide new mechanistic insights and unequivocally demonstrate a role of the already multifunctional CaMKII on the regulation of the NHE-1 activity. We found that activation of CaMKII during acidosis enhances the exchanger activity and in doing so, contributes to pHi recovery from an acid load. This stimulation was independent of and additive to ERK1/2 cascade, a well-known kinase-mediated mechanism for the acidosis-induced stimulation of NHE-1 activity. Besides its housekeeping role in the control of pHi homeostasis, the NHE-1 plays a causal or permissive role in the development of cardiac hypertrophy. In this scenario CaMKII is upregulated, therefore CaMKII-dependent NHE-1 activation could be a contributing factor to determine this pathological state